The designation xe2x80x9cxcex11Axe2x80x9d is the appellation recently approved by the IUPHAR Nomenclature Committee for the previously designated xe2x80x9cxcex11Cxe2x80x9d cloned subtype as outlined in the 1995 Receptor and Ion Channel Nomenclature Supplement (Watson and Girdlestone, 1995). However, the designation xcex11C is used throughout this application and the supporting tables and figures to refer to the receptor subtype recently renamed xe2x80x9cxcex11Axe2x80x9d. Since in both the old and new nomenclature there has only been one unique receptor subtype which has been designated xcex11C (i.e., there is no xcex11C under the current nomenclature), xe2x80x9cxcex11Cxe2x80x9d is an unambiguous description of this unique receptor subtype.
Benign Prostatic Hyperplasia (BPH), also called Benign Prostatic Hypertrophy, is a progressive condition which is characterized by a nodular enlargement of prostatic tissue resulting in obstruction of the urethra. This results in increased frequency of urination, nocturia, a poor urine stream and hesitancy or delay in starting the urine flow. Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection. The specific biochemical, histological and pharmacological properties of the prostate adenoma leading to the bladder outlet obstruction are not yet known. However, the development of BPH is considered to be an inescapable phenomenon for the aging male population. BPH is observed in approximately 70% of males over the age of 70. Currently, in the United States, the method of choice for treating BPH is surgery (Lepor, H., Urol. Clinics North Amer., 17, 651 (1990)). Over 400,000 prostatectomies are performed annually (data from 1986). A medicinal alternative to surgery is clearly very desirable. The limitations of surgery for treating BPH include the morbidity rate of an operative procedure in elderly men, persistence or recurrence of obstructive and irritative symptoms, as well as the significant cost of surgery.
xcex1-Adrenergic receptors (McGrath, et. al. Med. Res. Rev., 9, 407-533, 1989) are specific neuroreceptor proteins located in the peripheral and central nervous systems on tissues and organs throughout the body. These receptors are important switches for controlling many physiological functions and, thus, represent important targets for drug development. In fact, many xcex1-adrenergic drugs have been developed over the past 40 years. Examples include clonidine, phenoxybenzamine and prazosin (treatment of hypertension), naphazoline (nasal decongestant), and apraclonidine (treating glaucoma). xcex1-Adrenergic drugs can be broken down into two distinct classes: agonists (clonidine and naphazoline are agonists), which mimic the receptor activation properties of the endogenous neurotransmitter norepinephrine, and antagonists (phenoxybenzamine and prazosin are antagonists), which act to block the effects of norepinephrine. Many of these drugs are effective but also produce unwanted side effects (for example, clonidine produces dry mouth and sedation in addition to its antihypertensive effects).
During the past 15 years a more precise understanding of xcex1-adrenergic receptors and their drugs has evolved through increased scientific scrutiny. Prior to 1977, only one xcex1-adrenergic receptor was known to exist. Between 1977 and 1988, it was accepted by the scientific community that at least two xcex1-adrenergic receptorsxe2x80x94xcex11 and xcex12xe2x80x94existed in the central and peripheral nervous systems. Since 1988, new techniques in molecular biology have led to the identification of at least six xcex1-adrenergic receptors which exist throughout the central and peripheral nervous systems: xcex11A, xcex11B, xcex11C, xcex12A, xcex12B and xcex12C (Bylund, D. B., FASEB J., 6, 832 (1992)). In many cases, it is not known precisely which physiological responses in the body are controlled by each of these receptors. In addition, current xcex1-adrenergic drugs are not selective for any particular xcex1-adrenergic receptor. Many of these drugs produce untoward side effects which may be attributed to their poor xcex1-adrenergic receptor selectivity.
Since the mid 1970""s, nonselective xcex1-antagonists have been prescribed to treat BPH. In 1976, M. Caine, et al. (Brit. J. Urol., 48, 255 (1976)), reported that the nonselective xcex1-antagonist phenoxybenzamine was useful in relieving the symptoms of BPH. This drug may produce its effects by interacting with xcex1-receptors located on the prostate. However, this drug also produces significant side effects such as dizziness and asthenia which severely limit its use in treating patients on a chronic basis. More recently, the xcex1-adrenergic antagonists prazosin and terazosin have also been found to be useful for treating BPH. However, these drugs also produce untoward side effects. It has recently been discovered that the xcex11C receptor is responsible for mediating the contraction of human prostate smooth muscle (Gluchowski, C. et. al., WO 94/10989, 1994; Forray, C. et. al., Mol. Pharmacol. 45, 703, 1994). This discovery indicates that the xcex11C antagonists may be effective agents for the treatment of BPH with decreased side effects. Further studies have indicated that the xcex11C receptor may also be present in other lower urinary tract tissues, such as urethral smooth muscle (Ford et al. Br. J. Pharmacol., 114, 24P, (1995)).
This invention is directed to dihydropyrimidine compounds which are selective antagonists for cloned human xcex11C receptors. This invention is also related to uses of these compounds for lowering intraocular pressure (Zhan, et. al. Ophthalmol. Vis. Sci., 34 Abst. #1133, 928, 1993), inhibiting cholesterol synthesis (D""Eletto and Javitt, J. Cardiovascular Pharmacol. 13 (Suppl. 2) S1-S4, 1989), benign prostatic hyperplasia, impotency (Milne and Wyllie, EP 0 459 666 A2, 1991), sympathetically mediated pain (Campbell, WO 92/14453, 1992), cardiac arrhythmia (Spiers, et. al., J. Cardiovascular Pharmacol., 16, 824-830, 1990) and for the treatment of any disease where antagonism of the xcex11C receptor may be useful.
This invention is directed to dihydropyrimidine compounds which are selective antagonists for human xcex11C receptors. This invention is also related to uses of these compounds for lowering intraocular pressure, inhibiting cholesterol synthesis, relaxing lower urinary tract tissue, the treatment of benign prostatic hyperplasia, impotency, cardiac arrhythmia and for the treatment of any disease where antagonism of the xcex11C receptor may be useful. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.
The present invention is directed to compounds having the structures: 
where A is 
where each of Y1, Y2, Y3, Y4 and Y5 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; xe2x80x94OR3, xe2x80x94OCOR3, xe2x80x94COR3, xe2x80x94CONHR3, xe2x80x94CON(R3)2, or xe2x80x94COOR3; or any two of Y1, Y2, Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;
where X is S; O; or NR3;
where R1 is xe2x80x94H; xe2x80x94NO2; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2) pOR3; xe2x80x94COR3; xe2x80x94CO2R3; or xe2x80x94CON(R3)2;
where R2 is xe2x80x94H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-C1-C10-alkyl, C3-C10 cycloalkyl-C1-C10-monofluoroalkyl or C3-C10 cycloalkyl-C1-C10-polyfluoroalkyl; xe2x80x94CN; xe2x80x94CH2XR3, xe2x80x94CH2X(CH2)pNHR3, xe2x80x94(CH2)pNHR3, xe2x80x94CH2X(CH2)pN(R3)2, xe2x80x94CH2X(CH2)pN3 or xe2x80x94CH2X(CH2)pNHCXR7; or xe2x80x94OR3;
where each p is independently an integer from 1 to 7;
where each n is independently an integer from 0 to 5;
where each R3 is independently xe2x80x94H; straight chained or branched C2-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 
where Z is C2-C7 alkenylene or alkynylene; CH2; O; CO; CO2; CONR3; S; SO; SO2; or NR3;
where each D is independently CH2O; S; NR3; CO; or CS;
where W is Cxe2x95x90O; Cxe2x95x90NOR3; substituted or unsubstituted phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl, benzofurazanyl, benzofuranyl or benzyimidazolyl, where the phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl, benzofurazanyl, benzofuranyl or benzyimidazolyl is substituted with xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl, C3-C7 cycloalkenyl, xe2x80x94N(R3)2, xe2x80x94OR3, xe2x80x94COR3, xe2x80x94CO2R3, or xe2x80x94CON(R3)2;
where each V is independently O; S; CR5R7; C(R7)2; or NR7;
where each m is independently an integer from 0 to 3;
where o is an integer from 1 to 3;
where each R is independently xe2x80x94H; xe2x80x94F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; xe2x80x94N(R3)2; xe2x80x94NO2; xe2x80x94CN; xe2x80x94CO2R3; or xe2x80x94OR3;
where R5 is xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; phenyl, thiophenyl, pyridyl, pyrrolyl, furanyl, imidazolyl or indolyl; xe2x80x94COOR3, xe2x80x94COR3, xe2x80x94CONHR3, xe2x80x94CN, or xe2x80x94OR3;
where each R6 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; or xe2x80x94OR3;
where each R7 is independently xe2x80x94H; substituted or unsubstituted benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl, benzofurazanyl, benzofuranyl, benzimidazolyl or 2-keto-1-benzimidazolinyl, where the benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl, benzofurazanyl, benzofuranyl, benzimidazolyl or 2-keto-1-benzimidazolinyl is substituted with xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl, C3-C7 cycloalkenyl, xe2x80x94N(R3)2, xe2x80x94OR3, xe2x80x94COR3, xe2x80x94CO2R3, or xe2x80x94CON(R3)2; substituted or unsubstituted straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; substituted or unsubstituted straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl or cycloalkenyl, where the alkyl, monofluoroalkyl, polyfluoroalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is substituted with xe2x80x94H, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl, benzofurazanyl, benzofuranyl, benzimidazolyl; and
where R8 is xe2x80x94H; substituted or unsubstituted benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl, benzofurazanyl, benzofuranyl, benzimidazolyl or 2-keto-1-benzimidazolinyl, where the benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl, benzofurazanyl, benzofuranyl, benzimidazolyl or 2-keto-1-benzimidazolinyl is substituted with xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl, C3-C7 cycloalkenyl, xe2x80x94N(R3)2, xe2x80x94OR3, xe2x80x94COR3, xe2x80x94CO2R3, or xe2x80x94CON(R3)2; substituted or unsubstituted straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; substituted or unsubstituted straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl or cycloalkenyl, where the alkyl, monofluoroalkyl, polyfluoroalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is substituted with xe2x80x94H, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl, benzofurazanyl, benzofuranyl, benzimidazolyl, xe2x80x94N(R3)2, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2R3, xe2x80x94OR3; 
or a pharmaceutically acceptable salt thereof.
The invention also provides for the (xe2x88x92) and (+) enantiomers of the compounds described herein.
In those embodiments having the following structure 
presently preferred compounds include the following: 
In preferred embodiments, the compounds may have the structures: 
where V is selected from CR5R7 or NR7 and p is selected from 1-3.
The invention provides for the preferred embodiment having the following structures: 
The invention further provides that the compound has the following structures: 
The invention further provides that the compound has the structure: 
The invention further provides that the compound has the structures: 
In those embodiments having the following structure 
presently preferred compounds include the following: 
The invention provides for the preferred embodiment having the following structure: 
In those embodiments having the following structure 
presently preferred compounds include the following: 
The invention provides for the preferred embodiment having the following structure: 
where R5 is selected from xe2x80x94CO2CH3 or xe2x80x94H.
The present invention is directed to compounds having the structures: 
where A is 
where each of Y1, Y2, Y3, Y4 and Y5 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; xe2x80x94OR4, xe2x80x94OCOR4, xe2x80x94COR4, xe2x80x94CONHR4, xe2x80x94CON(R4)2, or xe2x80x94COOR4; or any two of Y1, Y2, Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;
where X is S; O; or NR4;
where B is xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, alkoxy or thioalkyl; straight chained or branched C2-C7 alkenyl; xe2x80x94SCH2C6H4OR4; xe2x80x94(CH2)nC6H5; xe2x80x94CH2X(CH2)nNHR4; xe2x80x94(CH2)nNHR; or xe2x80x94OR4;
where R1 is xe2x80x94H; xe2x80x94NO2; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R4)2; xe2x80x94OR4; xe2x80x94(CH2)pOR4; xe2x80x94COR4; xe2x80x94CO2R4; or xe2x80x94CON(R4)2;
where R2 is independent chained or branched C1-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-C1-C10-alkyl, C3-C10 cycloalkyl-C1-C10-monofluoroalkyl or C3-C10 cycloalkyl-C1-C10-polyfluoroalkyl; xe2x80x94CN; xe2x80x94CH2XR4, xe2x80x94CH2X(CH2) NHR4, xe2x80x94(CH2)nNHR4, xe2x80x94CH2X(CH2)pN(R4)2, xe2x80x94CH2X(CH2)pN3 or xe2x80x94CH2X(CH2)pNHCXR7; or xe2x80x94OR4;
where each p is independently an integer from 1 to 7;
where each n is independently an integer from 0 to 5;
where R3 is 
where Z is C2-C7 alkenylene or alkynylene; CH2; O; CO; CO2; CONR4; S; SO; SO2; or NR4;
where each D is independently CH2; O; S; NR4; CO; or CS;
where W is Cxe2x95x90O; Cxe2x95x90NOR4; substituted or unsubstituted phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl, benzofurazanyl, benzofuranyl or benzyimidazolyl, where the phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl, benzofurazanyl, benzofuranyl or benzyimidazolyl is substituted with xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl, C3-C7 cycloalkenyl, xe2x80x94N(R4)2, xe2x80x94OR4, xe2x80x94COR4, xe2x80x94CO2R4, or xe2x80x94CON(R4)2;
where each V is independently O; S; CR5R7; C(R7)2; or NR7;
where each m is independently an integer from 0 to 3;
where o is an integer from 1 to 3;
where each R4 is independently xe2x80x94H; xe2x80x94F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; xe2x80x94N(R4)2; xe2x80x94NO2; xe2x80x94CN; xe2x80x94CO2R4; or xe2x80x94OR4;
where each R4 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
where R5 is xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; phenyl, thiophenyl, pyridyl, pyrrolyl, furanyl, imidazolyl or indolyl; xe2x80x94COOR4, xe2x80x94COR4, xe2x80x94CONHR4, xe2x80x94CN, or xe2x80x94OR4;
where each R6 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; or xe2x80x94OR4;
where each R7 is independently xe2x80x94H; substituted or unsubstituted benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl, benzofurazanyl, benzofuranyl, benzimidazolyl or 2-keto-1-benzimidazolinyl, where the benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl, benzofurazanyl, benzofuranyl, benzimidazolyl or 2-keto-1-benzimidazolinyl is substituted with xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl, C3-C7 cycloalkenyl, xe2x80x94N(R4)2, xe2x80x94OR4, xe2x80x94COR4, xe2x80x94CO2R4, or xe2x80x94CON(R4)2; substituted or unsubstituted straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; substituted or unsubstituted straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl or cycloalkenyl, where the alkyl, monofluoroalkyl, polyfluoroalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is substituted with xe2x80x94H, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl, benzofurazanyl, benzofuranyl, benzimidazolyl; and
where R8 is xe2x80x94H; substituted or unsubstituted benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl, benzofurazanyl, benzofuranyl, benzimidazolyl or 2-keto-1-benzimidazolinyl, where the benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl, benzofurazanyl, benzofuranyl, benzimidazolyl or 2-keto-1-benzimidazolinyl is substituted with xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl, C3-C7 cycloalkenyl, xe2x80x94N(R4)2, xe2x80x94OR4, xe2x80x94COR4, xe2x80x94CO2R4, or xe2x80x94CON(R4)2; substituted or unsubstituted straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; substituted or unsubstituted straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl or cycloalkenyl, where the alkyl, monofluoroalkyl, polyfluoroalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is substituted with xe2x80x94H, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl, benzofurazanyl, benzofuranyl, benzimidazolyl, xe2x80x94N(R4)2, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2R4, xe2x80x94OR4; 
or a pharmaceutically acceptable salt thereof.
The invention further provides for the (xe2x88x92) and (+) enantiomers of the compounds described above.
In those embodiments having the following structure 
presently preferred compounds include the following: 
The invention provides for the preferred embodiments having the following structures: 
In those embodiments having the following structure 
presently preferred compounds include the following: 
The invention also provides for the following preferred embodiment having the structure: 
where R5 is selected from xe2x80x94H or xe2x80x94CO2CH3.
The invention further provides for a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described herein and a pharmaceutically acceptable carrier. In one embodiment the therapeutically effective amount is an amount from about 0.01 mg per subject per day to about 500 mg per subject per day, preferably from about 0.1 mg per subject per day to about 60 mg per subject per day and most preferably from about 1 mg per subject per day to about 20 mg per subject per day. The therapeutically effective amount is an amount from about 0.01 mg to about 500 mg.
In one preferred embodiment the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution. In another equally preferred embodiment, the pharmaceutically acceptable carrier is a solid and the composition is in the form of a powder or tablet. In a further embodiment, the pharmaceutical carrier is a gel and the composition is in the form of a suppository or cream.
In a preferred embodiment the compound of the pharmaceutical composition additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia. In a further embodiment the compound of the pharmaceutical composition additionally does not cause a fall in blood pressure in rats at a dosage of 10 micrograms of compound per kilogram per rat.
The invention provides a method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject one of the compounds described herein effective to treat benign prostatic hyperplasia. The invention further provides that the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia. In one embodiment the compound additionally does not cause a fall in blood pressure in rats at a dosage of 10 micrograms of compound per kilogram of rat. In one preferred embodiment the compound effects treatment of benign prostatic hyperplasia by relaxing lower urinary tract tissue and in particular where lower urinary tract tissue is urethral smooth muscle.
The invention further provides a method of treating a subject suffering from high intraocular pressure which comprises administering to the subject one of the compounds described herein effective to lower intraocular pressure.
The invention further provides a method of treating a subject suffering from a disorder associated with high cholesterol which comprises administering to the subject one of the compounds described herein effective to inhibit cholesterol synthesis.
The invention also provides a method of treating a disease which is susceptible to treatment by antagonism of the xcex11C receptor which comprises administering to the subject one of the compounds described herein effective to treat the disease.
The invention further provides a method of treating a subject suffering from impotency which comprises administering to the subject one of the compounds described herein effective to treat impotency.
The invention further provides a method of treating a subject suffering from sympathetically mediated pain which comprises administering to the subject one of the compounds described herein effective to treat sympathetically mediated pain.
The invention provides a method of treating a subject suffering from cardiac arrhythmia which comprises administering to the subject one of the compounds described herein effective to treat cardiac arrhythmia.
The invention provides a method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject one of the compounds described herein in combination with a 5 alpha-reductase inhibitor effective to treat benign prostatic hyperplasia. In one preferred embodiment the 5-alpha reductase inhibitor is finasteride.
A pharmaceutical composition comprising a therapeutically effective amount one of the compounds described herein in combination with a therapeutically effective amount of finasteride and a pharmaceutically acceptable carrier. In one preferred embodiment the therapeutically effective amount of one of the compounds described herein is an amount from about 0.01 mg to about 500 mg and the therapeutically effective amount of the finasteride is about 5 mg. In a more preferred embodiment the therapeutically effective amount one of the compounds described herein is an amount from about 0.1 mg to about 60 mg and the therapeutically effective amount of finasteride is about 5 mg. In a further embodiment of the invention the therapeutically effective amount of the one of the compounds described herein is an amount from about 1 mg to about 20 mg and the therapeutically effective amount of finasteride is about 5 mg.
The invention further provides a method of relaxing lower urinary tract tissue which comprises contacting the lower urinary tract tissue with an amount of one of the compounds described herein effective to relax lower urinary tract tissue. In one embodiment the lower urinary tract tissue is urethral smooth muscle.
The invention provides a method of relaxing lower urinary tract tissue in a subject which comprises administering to the subject an amount of one of the compounds described herein effective to relax lower urinary tract tissue. In one preferred embodiment the lower urinary tract tissue is urethral smooth muscle.
The invention provides for the use of the compounds described herein for the preparation of a pharmaceutical composition for lowering intraocular pressure, inhibiting cholesterol synthesis, and the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the xcex11C receptor may be useful. The invention provides for the use of the compounds described herein for the preparation of a pharmaceutical composition for relaxing lower urinary tract tissue and in particular urethral smooth muscle. The invention further provides for the use of any of compounds described herein for the preparation of a pharmaceutical composition, where the compound additionally does not cause a fall in blood pressure at dosages effective to lower intraocular pressure, to inhibit cholesterol synthesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the xcex11C receptor may be useful. Furthermore the invention provides that the compound used in the preparation of the pharmaceutical composition additionally does not cause a fall in blood pressure in rats at a dosage of 10 micrograms of compound per kilogram per rat.
The invention provides for the use of the compounds described herein in the preparation of a medicament for lowering intraocular pressure, inhibiting cholesterol synthesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the xcex11C receptor may be useful. The invention provides for the use of the compounds described herein in the preparation of a medicament for relaxing lower urinary tract tissue and in particular urethral smooth muscle. The invention further provides for the use of any of compounds described herein in the preparation of a medicament, where the compound additionally does not cause a fall in blood pressure at dosages effective to lower intraocular pressure, to inhibit cholesterol synthesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the xcex11C receptor may be useful. The invention further provides that the compound in the medicament additionally does not cause a fall in blood pressure in rats at a dosage of 10 micrograms of compound per kilogram per rat.
The invention provides for a drug which is useful for lowering intraocular pressure, inhibiting cholesterol synthesis, and the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the xcex11C receptor may be useful, the effective ingredient of the said drug being any of the compounds described herein. The invention further provides the drug described herein additionally does not cause a fall in blood pressure at dosages effective to lower intraocular pressure, to inhibit cholesterol synthesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the xcex11C receptor may be useful. The invention further provides that the drug additionally does not cause a fall in blood pressure in rats at a dosage of 10 micrograms of compound per kilogram per rat.
The invention provides for a drug which is useful for relaxing lower urinary tract tissue and in particular urethral smooth muscle, the effective ingredient of the drug being any of the compounds described herein. The invention further provides the drug which is useful for relaxing lower urinary tract tissue additionally does not cause a fall in blood pressure at dosages effective to relax lower urinary tract tissue. The invention further provides that the drug which is useful for relaxing lower urinary tract tissue additionally does not cause a fall in blood pressure in rats at a dosage of 10 micrograms of compound per kilogram per rat. The invention also provides for the (xe2x88x92) and (+) enantiomers of all compounds of the subject application described herein. Included in this invention are pharmaceutically acceptable salts and complexes of all of the compounds described herein. The salts include but are not limited to the following acids and bases. The following inorganic acids; hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid. The organic acids; acetic acid, trifluoroacetic acid, formic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid. The following inorganic bases; ammonia, hydroxyethylamine and hydrazine. The following organic bases; methylamine, ethylamine, propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine and guanidine. This invention further provides for the hydrates and polymorphs of all of the compounds described herein.
The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compounds described above and a pharmaceutically acceptable carrier. In the subject invention a xe2x80x9ctherapeutically effective amountxe2x80x9d is any amount of a compound which, when administered to a subject suffering from a disease against which the compounds are effective, causes reduction, remission, or regression of the disease. In one embodiment the therapeutically effective amount is an amount from about 0.01 mg per subject per day to about 500 mg per subject per day, preferably from about 0.1 mg per subject per day to about 60 mg per subject per day and most preferably from about 1 mg per subject per day to about 20 mg per subject per day. In the practice of this invention the xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d is any physiological carrier known to those of ordinary skill in the art useful in formulating pharmaceutical compositions.
The invention also provides for pharmaceutical composition comprising a therapeutically effective amount of the any of the compounds described herein in combination with a therapeutically effective amount of finasteride and a pharmaceutically acceptable carrier. In one embodiment the pharmaceutical composition is a therapeutically effective amount from about 0.01 mg per subject per day to about 500 mg per subject per day of any one of the compounds described herein and a therapeutically effective amount of the finasteride of about 5 mg per subject per day. A more preferred embodiment of the pharmaceutical composition is a therapeutically effective amount from about 0.1 mg per subject per day to about 60 mg per subject per day of any one of the compounds described herein and a therapeutically effective amount of the finasteride of about 5 mg per subject per day. The most preferred embodiment of the pharmaceutical composition is a therapeutically effective amount from about 1 mg per subject per day to about 20 mg per subject per day of any one of the compounds described herein and a therapeutically effective amount of the finasteride of about 5 mg per subject per day.
In one preferred embodiment the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution. In another equally preferred embodiment, the pharmaceutically acceptable carrier is a solid and the composition is in the form of a powder or tablet. In a further embodiment, the pharmaceutical carrier is a gel and the composition is in the form of a suppository or cream. In a further embodiment the compound may be formulated as a part of a pharmaceutically acceptable transdermal patch.
A solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium. Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
The compound can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents, for example, enough saline or glucose to make the solution isotonic, bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
The compound can also be administered orally either in liquid or solid composition form. Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.
The invention further provides a method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject an amount of the one the compounds described above effective to treat benign prostatic hyperplasia.
The invention also provides a method of treating a subject suffering from high intraocular pressure which comprises administering to the subject an amount of any of the compounds described above effective to lower intraocular pressure.
This invention also provides a method of treating a subject suffering a disorder associated with high cholesterol which comprises administering to the subject an amount of any of the compounds described above effective to inhibit cholesterol synthesis.
This invention also provides a method of treating a disease which is susceptible to treatment by antagonism of the xcex11C receptor which comprises administering to the subject an amount of any the compounds described above effective to treat the disease.
This invention also provides a method of treating a subject suffering from impotency which comprises administering to the subject an amount of any of the compounds described above effective to treat impotency.
This invention also provides a method of treating a subject suffering from sympathetically mediated pain which comprises administering to the subject an amount of any of the compounds described above effective to treat sympathetically mediated pain.
This invention also provides a method of treating a subject suffering from cardiac arrhythmia which comprises administering to the subject an amount of any of the compounds described above effective to treat cardiac arrhythmia.
This invention also provides a method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject an amount of any of the compounds described above in combination with a 5 alpha-reductase inhibitor effective to treat benign prostatic hyperplasia. The 5-alpha reductase inhibitor is finasteride. The dosage administered to the subject is about 0.01 mg per subject day to 50 mg per subject per day of finasteride in combination with an xcex11C antagonist. A preferred dosage administered to the subject is about 0.2 mg per subject per day to 10 mg per subject per day of finasteride in combination with an xcex11C antagonist. A more preferred dosage administered to the subject is about 1 mg per subject per day to 7 mg per subject per day of finasteride in combination with an xcex11C antagonist. The most preferred dosage administered to the subject is about 5 mg per subject per day of finasteride in combination with an xcex11C antagonist.
One skilled in the art will readily appreciate that appropriate biological assays will be used to determine the therapeutic potential of the claimed compounds for the treating the above noted disorders.
This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.